This invention relates to the preparation of phosphatase inhibitors that act as phosphotyrosine mimetics. The invention particularly relates to compounds designed to inhibit protein-tyrosine phosphatase 1B, and for the treatment of diabetes.
Protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) play an essential role in the regulation of various cellular functions including cell growth, proliferation, differentiation, metabolism and immune responses. They are therefore potentially important targets for therapeutic intervention in a number of diseases, including cancers and diabetes. PTKs generate phosphotyrosyl (pTyr) residues by mediating the phosphorylation of tyrosyl residues. PTPs, in turn, remove pTyr phophates and may play either positive or negative roles in cellular signal transduction.
At present, about 100 enzymes comprise the PTP family and each is either receptor-like or cytoplasmic. One such enzyme is PTP1B, a prototypic intracellular PTP that is expressed in many human tissues and is implicated as a negative regulator of insulin receptor signaling. Recent studies have shown that a correlation exists between levels of PTP1B and insulin resistance states, suggesting that PTP1B may play a role in the insulin resistance associated with diabetes and obesity. Apparently, PTP1B plays a vital role in the dephosphorylation of the insulin receptor. Further, a knockout study has revealed that mice lacking functional PTP1B exhibit increased sensitivity toward insulin and are resistant to obesity (Elchebly, M. et al., Science 1999, 283, 1544-1548). These studies suggest that PTP1B inhibitors would be useful in the treatment of insulin resistance and obesity. More importantly, such an inhibitor could function as an agent for the treatment of non-insulin dependent diabetes mellitus without inducing hypoglycemia.
To date, many of the previously reported PTP1B inhibitors have been peptide-based, containing negatively charged sulfate or phosphonic acid derivatives. Most of these compounds have been found to be inefficient in crossing cell membranes and are unstable in vivo. More recently, small organic molecules have been identified as potent and selective inhibitors of PTP1B (Larsen, S. et al. WO 00/53583; Larsen, S. et al., WO 99/11606; Sarmieto, M. et al., J. Med. Chem. 2000, 43, 146-155; Wrobel, J. et al., J. Med. Chem. 1999, 42, 3199-3202). Still desired is a PTP1B inhibitor that is even less peptidic in nature such that it increases solubility, absorption, cellular penetration and oral availability.
This invention provides certain tyrosine analogs of Formula I that are useful for treating Type II diabetes mellitus. Specifically, the present invention relates to compounds of Formula I that inhibit the protein tyrosine phosphatase 1B enzyme. Also provided are formulations containing compounds of Formula I and methods of using the compounds to treat a patient in need thereof. In addition, there are described processes for preparing the inhibitory compounds of Formula I.
The present invention relates to PTP1B inhibitors, pharmaceutically acceptable salts and prodrugs thereof useful in the therapeutic or prophylactic treatment of Type II diabetes mellitus. The invention also encompasses pharmaceutical compositions and methods for the treatment of Type II diabetes mellitus.
Accordingly, the compounds of the invention are members of the class of compounds of Formula I: 
wherein
R1 is selected from hydrogen, hydroxy, halogen, amino, monoalkylamino, trifluoromethyl, aminomethyl, cyano, nitro, xe2x80x94COOR6, and
heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8;
R2 is selected from hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, alkoxyalkyl, hydroxyalkyl, lower alkenyl, amino, mono- or dialkylamino, cyano, nitro, trifluromethyl, xe2x80x94CON(R6)2, xe2x80x94COOR6, and
aryl and heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8;
R3, R4, R5 are independently selected from hydrogen, hydroxy, halogen, lower alkyl, lower alkenyl, cycloalkyl, cyano, xe2x80x94CON(R6)2 and xe2x80x94COOR6, and
aryl and heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8;
A is selected from lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94C(O)R7, xe2x80x94S(O)2R7, xe2x80x94C(O)NHR7, xe2x80x94CO2R7, xe2x80x94(CH2)nS(O)qR7, xe2x80x94(CH2)pC(O)R7, xe2x80x94(CH2), pC(O)NHR7, xe2x80x94(CH2)pCO2R7, (CH2)nOR7, and
aryl, heteroaryl, arylalkyl, and heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8;
B is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, xe2x80x94(CH2)nS(O)qR7, xe2x80x94(CH2)pC(O)R7, xe2x80x94(CH2)pC(O)NHR7, xe2x80x94(CH2)pCO2R7, (CH2)nOR7, and
aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl and heteroarylalkynyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8;
n is 2-4;
p is 1-2;
q is 0-2;
R6 is selected from hydrogen, lower alkyl, and lower alkenyl;
R7 is selected from lower alkyl, or
aryl, heteroaryl, arylalkyl, and heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R8, COOR8, C(O)NHR8, and OR8; and
R8 is independently selected from hydrogen, and
lower alkyl, aryl and heteroaryl optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or dialkylamino, and trifluoromethyl.
The novel compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts and prodrugs thereof.
Preferred compounds of Formula I are those where R1 is selected from hydroxy, amino, mono-C1-2-alkylamino and xe2x80x94COOH; R2 is hydrogen; R3 is selected from hydrogen, fluoro and methyl; R4 is selected from hydrogen and xe2x80x94COOH; R5 is xe2x80x94COOH; A is selected from xe2x80x94C(O)R7 and xe2x80x94S(O)2R7; B is selected from lower alkyl, aryl-C2-6-alkyl, 5-6-membered heteroaryl-C2-6-alkyl, and (CH2)nOR7; R7 is selected from aryl, 5-6 membered heteroaryl, aryl-C1-3-alkyl, and heteroaryl-C1-3-alkyl; n is 2-4; and R8 is lower alkyl.
More preferred compounds of Formula I are those where R1 is selected from hydroxy, amino, and monomethylamino; R2 is hydrogen; R3 is selected from hydrogen and fluoro; R4 is hydrogen; R5 is xe2x80x94COOH; A is selected from xe2x80x94C(O)R7 and xe2x80x94S(O)2R7; B is selected from C4-6-alkyl, phenyl-C3-4-alkyl, 5-6 membered heteroaryl-C3-4-alkyl, and (CH2)nOR7; R7 is selected from phenyl, 5-6 membered heteroaryl, phenyl-C1-2-alkyl, and 5-6 membered heteroaryl-C1-2-alkyl; n is 2-4; and R8 is lower alkyl.
In addition to the compounds of Formula I, the invention encompasses compounds of Formula Ia: 
wherein R1, R2, R3, A and B are as defined above for Formula I.
Preferred compounds of Formula Ia are those where R1 is selected from amino and hydroxy; R2 is hydrogen; R3 is selected from hydrogen, fluoro and methyl; A is selected from xe2x80x94C(O)R7 and xe2x80x94S(O)2R7; B is selected from arylalkyl, heteroarylalkyl, and (CH2)nOR7; R7 is selected from aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and n is 2-4.
In addition, the invention encompasses compounds of Formula Ib: 
wherein R2, A and B are as defined above for Formula I.
Preferred compounds of Formula Ib are those where R2 is hydrogen; A is selected from xe2x80x94C(O)R7 and xe2x80x94S(O)2R7; B is selected from arylalkyl, heteroarylalkyl, and (CH2)nOR7; R7 is selected from aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and n is 2-4.
Further, the invention encompasses compounds of Formula Ic: 
wherein R2, R4, A and B are as defined above for Formula I.
Preferred compounds of Formula Ic are those where R2 is hydrogen; R4 is selected from xe2x80x94COOH and tetrazolyl; A is selected from xe2x80x94C(O)R7 and xe2x80x94S(O)2R7; B is selected from arylalkyl, heteroarylalkyl, and (CH2)nOR7; R7 is selected from aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and n is 2-4.
Except as expressly defined otherwise, the following definition of terms is employed throughout this specification.
By xe2x80x9calkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. More preferred alkyl radicals are C1-3 alkyl.
By xe2x80x9calkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, attached through a divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy. More preferred are C1-3 alkoxy.
By xe2x80x9calkylthioxe2x80x9d and xe2x80x9clower alkylthioxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, attached through a divalent sulfur atom, such as, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, and 3-methylpentylthio. More preferred are C1-3 alkylthio.
xe2x80x9cAlkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and at least one double bond and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. More preferred are lower alkenyl having 3-5 carbon atoms.
xe2x80x9cAlkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. More preferred are alkynyl having 3-5 carbon atoms.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine.
By xe2x80x9cheteroarylxe2x80x9d is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl. More preferred heteroaryl groups are 5-, or 6 membered radicals. Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, haloalkyl, aryl, heteroaryl, and hydroxy.
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, aryl, heteroaryl, and hydroxy.
The terms xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred aralkyl radicals are aryl-C1-3-alkyl. Examples include benzyl, phenylethyl, and the like.
The term xe2x80x9cheteroarylalkylxe2x80x9d means an alkyl moiety (as defined above) substituted with an heteroaryl moiety (also as defined above). More preferred heteroarylalkyl radicals are 5- or 6-membered heteroaryl-C1-3-alkyl. Examples include, oxazolemethyl, pyridylethyl and the like.
It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, for the formula xe2x80x94C(O)R7 where R7 is xe2x80x9calkylaminoxe2x80x9d, the structure is xe2x80x94C(O)-NH-alkyl; similarly, if R7 is xe2x80x9caminoalkylxe2x80x9d then the structure is xe2x80x94C(O)-alkyl-NH2.
The following abbreviations are used interchin the application.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d as used herein refers to an organic or inorganic salt which is useful in the treatment of a warm-blooded animal. Such salts can be acid or basic addition salts, depending on the nature of the compound of Formula I. As used herein, xe2x80x9cwarm blooded animalxe2x80x9d includes a mammal, including a member of the human, equine, porcine, bovine, murine, canine or feline species.
In the case of an acidic moiety in a compound of Formula I, a salt may be formed by treatment of a compound of Formula I with a basic compound, particularly an inorganic base. Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. An especially preferred salt is a sodium or potassium salt of a compound of Formula I.
With respect to basic moieties, a salt is formed by the treatment of a compound of Formula I with an acidic compound, particularly an inorganic acid. Preferred inorganic salts of this type may include, for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric or the like salts. Preferred organic salts of this type, may include, for example, salts formed with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, paratoluenesulfonic, sorbic, puric, benzoic, cinnamic and the like organic acids. An especially preferred salt of this type is a hydrochloride or sulfate salt of a compound of Formula I.
Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of Formula I. A metabolically labile ester is one that may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one that is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. Esters of a compound of Formula I, may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety. Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, xcex1-methoxyethyl, groups such as xcex1-((C1-4) alkyloxy) ethyl; for example, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-1,3,dioxolen-4-yl, etc.; C1-3-alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example, pivaloyloxymethyl, xcex1-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; or xcex1-acyloxy-xcex1-substituted methyl groups, for example xcex1-acetoxyethyl.
Additionally, the compounds of the instant invention may have one or more asymmetrical carbon atoms and, therefore, may exist in stereoisomeric forms. All stereoisomers are intended to be included within the scope of the present invention. As used, xe2x80x9cstereoisomerxe2x80x9d or xe2x80x9cstereoisomericxe2x80x9d refers to a compound which has the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped such that their orientation in three-dimensional space is different. Such stereoisomers may exist as enantiomeric mixtures, diastereomers or may be resolved into individual stereoisomeric components (e.g. specific enantiomers) by methods familiar to one skilled in the art.
Additionally the present invention includes all possible tautomers thereof.
Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as EtOH, DMF, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
In another aspect, the compounds of the invention are useful for the therapeutic or prophylactic treatment of Type II diabetes mellitus. The compounds of the invention may be also be used as PTP1B inhibitory agents in other diseases, such as, for example, different type of cancers, insulin resistance and obesity. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, bone, colon, adenocarcinoma, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkins, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system; and leukemia.
While it may be possible to administer a compound of the invention alone, normally it will be present as an active ingredient in a pharmaceutical formulation. Thus, in one another embodiment of the invention, there is provided a formulation comprising a compound of Formula I in combination, admixture, or associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.
The composition used in the noted therapeutic methods can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application. Considerations for preparing appropriate formulations will be familiar to one skilled in the art and are described, for example, in Goodman and Gilmans: xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, 8th Ed., Pergamon Press, Gilman et al. eds. (1990); and xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, 18th Ed., Mack Publishing Co., A. Gennaro, ed. (1990). Methods for administration are discussed therein, eq. for oral, topical, intravenous, intraperitoneal, or intramuscular administration. Pharmaceutically acceptable carriers, diluents, and excipients, likewise, are discussed therein. Typical carriers, diluents, and excipients may include water (for example, water for injection), buffers, lactose, starch, sucrose, and the like.
As noted, a compound of the invention can be administered orally, topically or parenterally (e.g. intravenously, intraperitoneally, intramuscularly, subcutaneously, etc.), or inhaled as a dry powder, aerosol, or mist, for pulmonary delivery. Such forms of the compounds of the invention may be administered by conventional means for creating aerosols or administering dry powder medications using devices such as for example, metered dose inhalers, nasal sprayers, dry powder inhaler, jet nebulizers, or ultrasonic nebulizers. Such devices optionally may be include a mouthpiece fitted around an orifice. In certain circumstances, it may be desirable to administer the desired compound of the invention by continuous infusion, such as through a continuous infusion pump, or using a transdermal delivery device, such as a patch.
In a further embodiment of the invention, there is provided a pharmaceutical preparation for topical application comprising a compound of the invention, typically in concentrations in the range of from about 0.001% to about 10%, in combination with a pharmaceutically acceptable carrier, excipient, or diluent therefor. Such topical preparations can be prepared by combining the compound of the invention with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations. Ointment and creams may be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Such bases may include water and/or an oil such as a liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents which may be used according to the characteristics of the base may include, for example, soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin, beeswax, and the like.
Lotions may be formulated with an aqueous or oily base and will include also, in general, one or more of the following: stabilizing agents emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like. Powders may be formed with the aid of any suitable powder bases, for example, talc, lactose, starch and the like. Drops may be formulated with an aqueous base or non-aqueous base also comprising one or more dispersing agents, suspending agents solubilizing agents, and the like.
Any of the formulations of the invention may also include one or more preservatives or bacteriostatic agents, for example, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like. Additionally, the formulations may contain other active ingredients such as antimicrobial agents, particularly antibiotics, anesthetics, analgesics and antipruritic agents.
The pharmaceutical formulations of the invention may be administered by parenteral or oral administration for prophylactic and/or therapeutic treatment. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration may include powders, tablets, pills, capsules and dragxc3xa9es.
The pharmaceutical formulations can be administered intravenously. Therefore, the invention further provides formulations for intravenous administration, which comprise a compound of the invention dissolved or suspended in a pharmaceutically acceptable carrier or diluent therefor. A variety of aqueous carriers can be used, for example, water, buffered water or other buffer solutions, saline, and the like. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The sterile aqueous solution for the lyophilized product can be packaged as a kit for use with the lyophilized formulation. The compositions can contain pharmaceutically acceptable substances to aid in administration and more closely mimic physiological conditions. Such substances, can include, for example, pH adjusting substances such as acids, bases or buffering agents, tonicity adjusting agents, wetting agents and the like. Such substances may include but are not limited to, for example, sodium hydroxide, HCl, sulfuric acid, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, and the like or any other means familiar to one skilled in the art for maintaining pH at a desired level.
For solid formulations, carriers, diluents, and excipients known to one skilled in the art may be used. Such carriers, diluents and excipients may include, for example, mannitol, lactose, starch magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, or other solid polyol sugar, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable formulation is prepared by admixing any of the usual carrier, diluents, and excipients, such as those noted, with from about 0.1 to about 95% of a compound of the invention.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
Representative compounds of the present invention, which are encompassed by Formula I include, but are not limited to the compounds of the examples and their pharmaceutically acceptable acid or base addition salts or prodrugs thereof.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.
An illustration of the preparation of compounds of the present invention is shown in Schemes 1-5. A, B, R1, R2, R3, R4 and R5 are as described above for Formula I and X is a leaving group. 
As shown in Scheme 1, an N-carbobenzyloxy tyrosine II can be subject to standard peptide coupling conditions, such as, EDC in the presence of an amine III to form the corresponding amide IV. The phenol of the amide IV can be alkylated with a group V that in the presence of a base such as KOH forms the ether VI. This compound can be deprotected using for example, catalytic hydrogenation, to yield the free amine VII. The amine VII can be alkylated with a halide VIII to afford a compound of the Formula I. A compound of Formula I may be interconverted within the definitions of R2, R3, R4 or R5 to provide related examples with the same generic Formula I. For example, when R5 is carboxylate, it can be obtained from the corresponding ester or nitrile.
In certain embodiments of the invention, R1 and/or R2 have to be introduced onto the tyrosine-phenyl ring. For example, Scheme 2 depicts the synthetic route of compounds of the invention wherein R1 is a carboxylate and is prepared from the corresponding halide. 
As shown in Scheme 2, the amine and acid groups of iodo tyrosine IX can be protected, respectively, to form X and then XI. The protected tyrosine XI can then be converted to the carboxylate XII by, for example, treatment with CO, acetonitrile, a base and a catalyst such as a palladium catalyst. The phenol of XII can be alkylated with, for example, bromomethyl acetate to form XIII, which can subsequently be deprotected to produce the free acid XIV. The free acid XIV can then be subjected to standard peptide coupling conditions, such as, for example, EDC in the presence of an amine III to form the corresponding amide XV. XV can be further deprotected to the amine XVI which in turn can be reacted with a halide VIII to yield XVII. XVII can then be hydrolized to form compound XVIII.
Additional embodiments are described wherein the tyrosine ring is functionalized with an aniline. For example, Scheme 3 depicts the synthesis of compounds of the structure shown below where R1xe2x95x90NH2 and R5xe2x95x90CO2K 
As shown in Scheme 3, derivatization of the free amino acid XIX with a reagent, Axe2x80x94X in the presence of a base can provide a compound of formula XX. Coupling using standard coupling agents, such as EDC, with an amine, Bxe2x80x94NH2, can then provide XXI. Alklylation of the phenol can be accomplished with a group V that in the presence of a suitable base can form the ether XXII. Where R5 is a nitrile or ester, aqueous hydrolysis can provie the acid XXIII. Reduction using catalytic hydrogenation with a metal such as palladium on carbon with hydrogen or phase transfer hydrogenation can provide the anilino carboxylate salt XXIV.
Additional embodiments are described wherein the tyrosine ring is functionalized with a phenol. For example, Scheme 4 depicts chemistry that can be used to generate compounds wherein R1xe2x95x90OH, R5xe2x95x90CO2H and Axe2x95x90COR7. 
As shown in Scheme 4 selective protection of the diol XXV can be accomplished to provide phenol XXVI. Ehrylenmeyer condensation with an acid such as hippuric acid followed by the addition of an amine, Bxe2x80x94NH2, can provide a compound of formula XXVII. Alklylation of the phenol can be accomplished with a group V that in the presence of a suitable base can form the ether XXVIII. Where R5 is a nitrile or ester, aqueous hydrolysis can provie the acid XXIX. Reduction using catalytic hydrogenation with a metal such as palladium on carbon with hydrogen or phase transfer hydrogenation can provide the phenol carboxylic acid XXX.
Scheme 5 depicts chemistry that can be used to generate compounds wherein R1xe2x95x90OH, R5xe2x95x90CO2H and Axe2x95x90SO2R7. 
As shown in Scheme 5 persulfonylation of a compound of formula XXXI can provide a compound of formula XXXII. Amide bond formation using standard coupling conditions such as EDC in the presence of an amine, Bxe2x80x94NH2, can provide an amide XXXIII. Partial deprotection can provide regiomeric mixture of phenols of formula XXXIV. Benzyl protection followed by basic hydrolysis can provide a phenol of formula XXXVI. Alklylation of the phenol can be accomplished with a group V that in the presence of a suitable base can form the ether XXXVII. Where R5 is a nitrile or ester, aqueous hydrolysis followed by reduction using catalytic hydrogenation can provide the phenol carboxylic acid XXXVIII.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
Representative examples of methods for preparing intermediates of the invention are set forth below.